Design, synthesis, and pharmacological evaluation of novel benzothiazole derivatives targeting LCK in acute lymphoblastic leukemia

[Display omitted] •The synthesis process of LCK inhibitors and the screening of specific targeting LCK activity were described in detail.•The LCK inhibitors 7 m induces G2/M arrest in Jurkat cells and MOLT-4 cells.•The LCK inhibitors 7 m induces apoptosis in ALL cells.•The LCK inhibitors 7 m inhibits the phosphorylation of LCK and exerts the potential of treating ALL. Lymphocyte-specific protein tyrosine kinase (LCK), a member of the Src family of tyrosine kinases, is implicated in the pathogenesis of almost all types of leukemia via T cells activation and signal transduction. LCK is highly expressed in acute lymphoblastic leukemia (ALL), and knockdown of the LCK gene can significantly inhibit the proliferation of leukemia cell lines. Here, we designed and synthesized a series of benzothiazole derivatives as novel LCK inhibitors using both docking-based virtual screening and activity assays for structural optimization. Among these compounds, 7 m showed a strong inhibitory activity in the proliferation of leukemia cell lines and LCK kinase activity. Moreover, we found that compound 7 m could induce apoptosis while simultaneously blocking cell cycle via decreasing its phosphorylation at Tyr394 of the LCK. Collectively, these findings shed new light on compound 7 m that would be utilized as a promising drug candidate with apoptosis-triggered and cell cycle arrest activities for the future ALL therapy.